title: AMPA receptor-induced local brain-derived neurotrophic factor signaling mediates motor recovery after stroke.
abstract: Stroke is the leading cause of adult disability. Recovery after stroke shares similar molecular and cellular properties with learning and memory. A main component of learning-induced plasticity involves signaling through AMPA receptors (AMPARs). We systematically tested the role of AMPAR function in motor recovery in a mouse model of focal stroke. AMPAR function controls functional recovery beginning 5 d after the stroke. Positive allosteric modulators of AMPARs enhance recovery of limb control when administered after a delay from the stroke. Conversely, AMPAR antagonists impair motor recovery. The contributions of AMPARs to recovery are mediated by release of brain-derived neurotrophic factor (BDNF) in periinfarct cortex, as blocking local BDNF function in periinfarct cortex blocks AMPAR-mediated recovery and prevents the normal pattern of motor recovery. In contrast to a delayed AMPAR role in motor recovery, early administration of AMPAR agonists after stroke increases stroke damage. These findings indicate that the role of glutamate signaling through the AMPAR changes over time in stroke: early potentiation of AMPAR signaling worsens stroke damage, whereas later potentiation of the same signaling system improves functional recovery.
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA.
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Clarkson
authors.forename: Justine J
authors.initials: JJ
authors.lastname: Overman
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhong
authors.forename: Rudolf
authors.initials: R
authors.lastname: Mueller
authors.forename: Gary
authors.initials: G
authors.lastname: Lynch
authors.forename: S Thomas
authors.initials: ST
authors.lastname: Carmichael
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism / Q000503:physiopathology; D004594:Electrophysiology; D004797:Enzyme-Linked Immunosorbent Assay; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009048:Motor Skills / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D020318:Rats, Long-Evans; D018091:Receptors, AMPA / Q000378:metabolism*; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020521:Stroke / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018690:Excitatory Amino Acid Agonists; D018091:Receptors, AMPA